Optically active nitro alcohol derivatives, optically active amino alcohol derivatives, and process for preparing the same

ABSTRACT

Optically active 1-substituted phenyl-2-nitro alcohol derivatives having the formula (1)                    
     and the process for producing thereof, and 1-substituted phenyl-2-amino alcohol derivatives having the formula (2)                    
     and the process for producing thereof from the optically active 1-substituted phenyl-2-nitro alcohol derivatives. From these nitro alcohols, pharmaceuticals such as (R)-albutamin and (R)-sarmeterol useful as a bronchodilator is obtained via optically active amino alcohols which are useful pharmaceutical intermediates.

TECHNICAL FIELD

The present invention relates to optically active 1-substitutedphenyl-2-nitro alcohol derivatives and the process for producingthereof, to optically active 1-substituted phenyl-2-amino alcoholderivatives and the process for producing thereof, and to the processfor producing (R)-albutamin and (R)-sarmeterol using these compounds.

The optically active nitro alcohols of the present invention are usefulin the medical field, particularly as a synthetic intermediate ofnitrogenous compounds useful for thrombotic diseases, for example,cerebral infarction, myocardial infarction, angina pectoris, andperipheral arterial occlusion; of optically active albuterol, opticallyactive sarmeterol, (R)-albutamin, and optically active terbutalinehydrochloride which are useful as a bronchodilator; and of opticallyactive bamethan sulfate useful as a vasodilator. And these compounds canbe produced in high yields and industrially advantageously with theprocess for producing thereof of the present invention.

The optically active amino alcohols of the present invention can beobtained from the above optically active nitro alcohols, and they arealso useful intermediates of pharmaceuticals such as a thrombolyticagent, a central nervous system agent, an antiadipogenous agent and anantiasthmatic agent.

BACKGROUND ART

The optically active nitro alcohols of the present invention are novelsubstances obtained by the nitro-aldol reaction between nitromethane andbenzaldehyde derivatives.

It is widely known that such a nitro-aldol reaction proceeds intheipresence of a base. For example, in Japanese Patent ApplicationLaid-Open No. 58-203950, there is disclosed the nitro-aldol reactionperformed in the presence of triethylamine which gives a racemicmodification of benznitro alcohol. And in Tetrahedron Letters (1975)p.4057, there is disclosed the reaction between 2-chlorobenzaldehyde andnitroethane under a catalyst of an optically active compound which givesan asymmetric nitro alcohol in which a substituent is a chloride.

Further, the present inventors has reported in Tetrahedron Letters(1993) Vol. 34, p. 2657 that the reaction between benzaldehyde andnitromethane under a catalyst of lanthanum-lithium-(R)-binaphtholcomplex at −50° C. gives (S)-1-phenyl-2 nitro ethanol in a yield of 84%(40% e.e.), and when carried out under a catalyst ofsamarium-lithium-(R)-binaphthol complex at −40° C., the reaction givesthe same compound in a yield of 90% (62% e.e.) ((R) or (S) in the nameof leach compound represents R or S isomer, respectively, showing thecompound's configuration).

The yields and optical purities described above, however, are notsatisfactory ones. In addition, an asymmetric nitro-aldol reaction ofbenzaldehyde compounds having a hydroxyl group or those having ahydroxyl group with a protecting group has not been found yet and thereaction products, optic ally active 1-substituted phenyl-2-nitroalcohol derivatives, have not been known yet, either.

But at the same time, it is hoped now that pharmaceuticals produced frombenznitro alcohol derivatives will be supplied in the form of a singleoptical isomer rather than in the form of a racemic modification. Thereason is that, when only one type of structure is therapeuticallyeffective, the other type of optically active substance is no betterthan impurities and likely to cause adverse effects. In order to meetsuch a demand, various types of asymmetric synthesis and opticalresolution of a racemic modification have been carried out as a methodof obtaining pharmaceuticals of optically active substances.

However, as described above, the nitro-group containing compounds(intermediates) of the present invention have not been known yet, andthe only example is (S)-1-phenyl-2-nitroethanol, which has nosubstituent, reported by the present inventors. Accordingly, the processfor producing a group of pharmaceuticals which are to be produced fromoptically active 1-substituted phenyl-2-nitro alcohol derivatives hasnot been known, either.

The optically active 1-substituted phenyl-2-amino alcohol derivatives ofthe present invention are a group of the compounds obtained from thenovel optically active 1-substituted phenyl-2-nitro alcohol derivativesof the present invention.

On the other hand, as a method of producing optically active1-substitute phenyl-2-amino alcohol derivatives, various types ofasymmetric synthesis and optical resolution of a racemic modificationhave been carried out, and various processes for producing compoundssimilar to these ones have been also reported.

For example, as a method using optical resolution, in Japanese PatentApplication Laid-Open No. 64-9979 (Japanese Patent Publication No.4-48791), there is disclosed a method of producing (R) isomer of2-amino-1-(3-chlorophenyl) ethanol from the racemic modification usingN-(t-butoxycarbonyl)-D-alanine. And in Japanese Patent ApplicationLaid-Open No. 2-85247, there is disclosed the method of subjecting theracemic modification of 2-amino-1-(4-chlorophenryl) ethanol to opticalresolution using D-tartaric acid.

As a method using an asymmetric reduction reaction, for example, inChemical and Pharmaceutical Bulletin (1995) vol. 43-5, p.738, there isdisclosed the process for producing (S)-1-phenyl-2-[N-(2-chloroethyl)]aminoethanol hydrochloride from 2-[N-(2-chloroethyl)] aminophenonehydrochloride.

And as a method using microorganisms, for example, in Chemistry Express(1989) vol. 4-9, p.621, there is disclosed the process for producingoptically active 2-amino-1-phenylethanol from 2-amino-1-phenylethanoland α-aminoacetophenone as raw materials by microorganisms ofStaphyrococcus, Micrococcus, Rhodococcus, and Niseria.

Further, in Japanese Patent Application Laid-Open No. 8-98697, there isdisclosed the process for producing optically active2-amino-1-phenylethanol derivatives from 2-amino-1-phenylethanolderivatives using various microorganisms.

With the method using optical resolution, however, even if opticalresolution is carried out perfectly, the maximum yield expected is only50% per reaction, and moreover, it is difficult to collect the opticallyactive substances desired in a good yield. Accordingly, in order toimprove the yield of optically active substances, it becomes necessaryto further racemize unnecessary chiral compounds and to carry outoptical resolution of the obtained racemic modifications repeatedly.Thus, using optical resolution can not produce the optically activesubstances desired effectively and industrially, therefore it can not bea satisfactory method.

Further, with the method using a usual hydrogen-reduction reaction ofwhich typical example is the above asymmetric reduction reaction, unlessthe hydrogen pressure is high, the reaction often does not proceed. Thusthe method is not appropriate, and moreover, since it has to use aspecial catalyst, the treatment of the catalyst has been a problem.

For the reduction reaction of optically active nitro alcohols, U.S. Pat.No. 5,099,067 reports that the reduction reaction of erythro/threo formsof β-nitro alcohol proceeds at room temperature by adding ammoniumformate.

For example, in Japanese Patent Application Laid-Open No. 6-256270, thepresent inventors report that (S)-(−) -propranolol is obtained in ayield of 90% from (S)-3-(α-naphthoxy)nitropropane-2-ol in the presenceof PtO₂ at 50° C. under atmospheric pressure. Further, the presentinventors report in Journal of the Organic Chemistry (1995) vol. 60, p.7388 that 2-amino-1,3-alkyldiol is obtained in a yield of 71% in thepresence of Pd—C.

These reduction reactions, however, are limited to the cases where thereduction reaction occurs on racemic modifications, and where, when thereaction occurs on optically active substances, a phenyl group has nosubstituent or only chlors as a substituent. There is no prior art knownwhich is related directly to the reduction reaction intended by thepresent invention during which a steric structure of phenyl group havinga hydroxyl group is maintained.

A racemic modification of 1-phenyl-2-aminoethanol is a known compound,for example, in Japanese Patent Application Laid-Open No. 58-203950,there is disclosed the synthetic method in which1-(3,4-dihidroxyphenyl)-2-nitroethanol is subjected to a catalytichydrogen addition reaction using Raney nickel to proceed the reductionreaction quantitatively, so as to obtain a racemic modification of1-(3,4-dihidroxyphenyl)-2-aminoethanol; however, the disclosure makes noconcrete reference to the optically active substances of 1-substitutedphenyl-2-aminoethanol.

Thus, optically active 1-substituted phenyl-2-nitroethanol derivativeshave not existed to date, and the products obtained by the reduction ofthe nitro group thereof, optically active 1-substitutedphenyl-2-aminoethanol derivatives, have not been produced.

On the other hand, 1-substituted phenyl-2-aminoethanol derivatives arewidely known compounds as a useful pharmaceutical intermediate.

For example, European Patent No. 0,006,735 specification describes thatthe intended pharmaceuticals can be synthesized by reacting a racemicand optically active amino alcohol compound with a carbonyl compound ora halide; however, actually disclosed in its embodiments is only theprocess for producing racemic sarmeterol by reacting a racemic aminoalcohol compound with a carbonyl compound or a halide.

In U.S. Pat. No. 5,442,118 specification there is disclosed the processfor producing (R)-albuterol and in European Patent Publication No.0,422,889 specification there is disclosed the process for producing(R)-sarmeterol; however, their production process is long, and theintended compound is obtained from the optically active styrene oxanederivatives which have been obtained from acetophenone derivatives as araw material. In these patents, there is no embodiment in which theoptically active 1-substituted phenyl-2-nitroethanol derivatives of thepresent invention are used.

Thus, optically active 1-substituted phenyl-2-nitroethanol compoundshave not existed to date, therefore, the process for producing opticallyactive albutamin and optically active sarmeterol using optically activecatechol amines obtained by the reduction of the nitro group thereof hasnot been known.

DISCLOSURE OF THE INVENTION

The present invention has been made in light of the foregoing problemsof the prior arts. Accordingly, it is an object of the present inventionto provide optically active 1-substituted phenyl-2-nitro alcoholderivatives and optically active 1-substituted phenyl-2-amino alcoholderivatives obtained by reducing the optically active 1-substitutedphenyl-2-nitro alcohol derivatives of the present invention both ofwhich are useful as an intermediate of pharmaceuticals such as(R)-albutamin, (R)-sarmeterol, (R)-albuterol and (R)-terbutalinehydrochloride which are useful as a bronchodilator, and bamethan sulfatewhich is useful as a vasohypotonic. Another object of the presentinvention is to provide a process for producing these compounds. Andanother object of the present invention is to provide (R)-albutamin and(R)-sarmeterol produced using these compounds.

After concentrating their energy on the study to achieve the aboveobjects, the present inventors came to know that, for the opticallyactive nitro alcohol derivatives, a group of the intended compounds canbe obtained using the group of rare earth metal complexes described bythemselves in U.S. Pat. No. 5,336,653 specification and TetrahedronLetters (1993) vol. 341 p. 2657 etc. At the same time, the presentinventors came to know that, for the optically active amino alcoholderivatives, a group of the intended compounds can be easily obtained bysubjecting the optically active nitro alcohol derivatives obtained asabove to catalytic hydrogen addition in an organic solvent. And thepresent inventors found that they can achieve the above objects withthese knowledge and have finally completed the present invention.

Specifically, the optically active 1-substituted phenyl-2-nitro alcoholderivatives of the present invention are characterized by the followingformula (1),

in which n and ml represent the positive integers satisfying 0<n+m≦5; R₁and R₂ represent a hydrogen atom or a hydroxyl-protective group,respectively, and when n+m is 2 or more, R₁ and R₂ can either beindependent of each other or form a ring among R₁s, R₂s, or R₁s plusR₂s; R₃ represents —(CH₂)₁—, in which 1 is 1, 2 or 3; R₄ represents ahydrogen atom, an alkyl group, or a hydroxymethyl group.

Suitable examples of the optically active1-(3,4-dihydroxyphenyl)-2-nitro alcohols of the present invention arecharacterized by the following formula (1-1),

in which R₅ and R₆ represent a hydrogen atom or a hydroxyl-protectivegroup, respectively, and they can either be independent of each other orform a ring; R₄ represents a hydrogen atom, an alkyl group, or ahydroxymethyl group.

(R)-albutamin etc., useful as a pharmaceutical, can be produced from thecompounds of the above group of which R₄ is a hydrogen atom and isomertype is R-type, by converting the nitro group into an amino group,reacting the amino group with a carbonyl compound or an alkyl halidecompound, and then eliminating the hydroxyl-protective group.

Suitable examples of the optically active1-(3-hydroxymethyl-4-hydroxyphenyl)-2-nitro alcohols of the presentinvention are characterized by the following formula (1-2),

in which R₁ and R₂ represent a hydrogen atom or a hydroxyl-protectivegroup, respectively, and they can either be independent of each other orform a ring; R₄ represents a hydrogen atom, an alkyl group, or ahydroxymethyl group.

(R)-sarmeterol, (R)-albuterol etc., useful as a pharmaceutical, can beproduced from the compounds of the above group of which R₄ is a hydrogenatom and isomer type is R-type, by converting the nitro group into anamino group, reacting the amino group with a carbonyl compound or analkyl halide compound, and then eliminating the hydroxyl-protectivegroup.

Suitable examples of the optically active1-(3,5-dihydroxyphenyl)-2-nitro alcohols of the present invention arecharacterized by the following formula (1-3),

in which R₁ and R₂ represent a hydrogen atom or a hydroxyl-protectivegroup, respectively, and they can either be independent of each other orform a ring; R₄ represents a hydrogen atom, an alkyl group, or ahydroxymethyl group.

Optically active terbutaline etc., useful as a bronchodilator, can beproduced from the compounds of the above group of R₄ is a hydrogen atom,by converting the nitro group into an amino group, reacting the aminogroup with a carbonyl compound or an alkyl halide compound, and theneliminating the hydroxyl-protective group.

Suitable examples of the optically active 1-(4-hydroxyphenyl)-2-nitroalcohols of the present invention are characterized by the followingformula (1-4),

in which R₁ represents a hydrogen atom or a hydroxyl-protective group,respectively, and it can either be independent of each other or form aring; R₄ represents a hydrogen atom, an alkyl group, or a hydroxymethylgroup.

Optically active bamethan etc., useful as a vasohypotonic, can beproduced from the compounds of the above group of which R₄ is a hydrogenatom, by converting the nitro group into an amino group, reacting theamino group of the amino alcohol with a carbonyl compound or an alkylhalide compound, and then eliminating the hydroxyl-protective group.

Other suitable examples of the optically active nitro alcohols of thepresent invention are as follows.

The optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivatives(optically active1-(3,4-di(t-butyldimethylsilolxy)phenyl)-2-nitroethanol) of formula(1-1), in which R₄ is a hydrogen atom, and each of R₅ and R₆ is at-butyldimethylsiloxy group.

Optically active albutamin etc. useful as a pharmaceutical can beproduced from this compound by converting the nitro group into an aminogroup, reacting the optically active amino alcohol with a carbonylcompound (for example, 4-(4-methoxymethoxyphenyl)butanoic acid, etc.),and then eliminating the hydroxyl-protective group.

The optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivatives(optically active 1-(3,4-dimethoxyphenyl)-2-nitroethanol) of formula(1-1), in which R₄ is a hydrogen atom, and each of R₅ and R₆ is a methylgroup.

Optically active albutamin etc. useful as a pharmaceutical can beproduced from this compound by converting the nitro group into an aminogroup, reacting the amino alcohol with a carbonyl compound (for example,4-(4-methoxymethoxyphenyl)butanoic acid, etc.), and then eliminating thehydroxyl-protective group.

The optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivatives(optically active 1-(3,4-dibenzyloxyphenyl)-2-nitroethanol) of formula(1-1), in which R₄ is a hydrogen atom, and each of R₅ and R₆ is a benzylgroup.

Optically active albutamin etc. useful as a pharmaceutical can beproduced from this compound by converting the nitro group into an aminogroup, reacting the optically active amino alcohol with a carbonylcompound (for example, 4-(4-methoxymethoxyphenyl)butanoic acid, etc.),and then eliminating the hydroxyl-protective group.

The optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivatives(optically active 1-(3,4-diacetoxyphenyl)-2-nitroethanol) of formula(1-1), in which R₄ is a hydrogen atom, and each of R₅ and R₆ is anacetyl group.

Optically active albutamin etc. useful as a pharmaceutical can beproduced from this compound by converting the nitro group into an aminogroup, reacting the optically active amino alcohol with a carbonylcompound (for example, 4-(4-methoxymethoxyphenyl)butanoic acid, etc.),and then eliminating the hydroxyl-protective group.

The optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivatives(optically active α-nitromethyl-piperonyl alcohol) of formula (1-1), inwhich R₄ is a hydrogen atom, and R₅ and R₆ are cyclized with a methylenegroup.

Optically active albutamin etc. useful as a pharmaceutical can beproduced from this compound by converting into an amino group, reactingthe optically active amino alcohol with a carbonyl compound (forexample, 4-(4-methoxymethoxyphenyl)butanoic acid, etc.), and theneliminating the hydroxyl-protective group.

The optically active2,2-dimethyl-α-nitromethyl-1,3-benzodioxan-6-methanol of formula (1-2),in which R₄ is a hydrogen atom, and R₁ and R₂ are cyclized.

Optically active sarmeterol etc. useful as a pharmaceutical can beproduced from this compound by converting into an amino group, reactingthe amino group with a carbonyl compound, and then eliminating thehydroxyl-protective group.

The optically active 1-(3,5-dibenzyloxyphenyl)-2-nitroethanol of formula(1-3), in which R₄ is a hydrogen atom, and each of R₁ and R₂ is a benzylgroup.

Optically active terbutaline etc. useful as a pharmaceutical can beproduced from this compound by converting into an amino group, reactingthe amino group with a carbonyl compound, and then eliminating thehydroxyl-protective group.

The optically active 1-(4-benzoyloxyphenyl)-2-nitroethanol of formula(1-4) set forth in claim 1, characterized in that R₄ is a hydrogen atomand R₁ is a benzoyl group. Optically active bamethan etc. useful as apharmaceutical can be produced from this compound by converting into anamino group, reacting the amino group with a carbonyl compound, and theneliminating the hydroxyl-protective group.

The process for stereoselectively producing optically active nitroalcohols of the present invention is characterized in that, whenproducing optically active 1-substituted phenyl-2-nitro alcoholderivatives, an aldehyde of the following formula (2),

in which R₅ and R₆ represent a hydrogen atom or a hydroxyl-protectivegroup, respectively, and they can either be independent of each other orform a ring together; R₄ represents a hydrogen atom, an alkyl group, ora hydroxymethyl group,

is reacted with a nitro alkane derivative of the following formula (3),

R₄—CH₂—NO₂  (3)

in which R₄ represents a hydrogen atom, an alkyl group, or ahydroxymethyl group,

in the presence of a rare earth metal complex having an optically activeligand.

Likewise, the process for stereoselectively producing optically activenitro alcohols of the present invention is characterized in that, whenproducing optically active 1-(3,4-dihydroxyphenyl)-2-nitro alcoholderivatives, an aldehyde of the following formula (2-1),

in which R₅ and R₆ represent a hydrogen atom or a hydroxyl-protectivegroup, respectively, and they can either be independent of each other orform a ring together; R₄ represents a hydrogen atom, an alkyl group, ora hydroxymethyl group, is reacted with a nitro alkane derivative of thefollowing formula (3),

R₄—CH₂—NO₂  (3)

in which R₄ represents a hydrogen atom, an alkyl group, or ahydroxymethyl group,

in the presence of a rare earth metal complex having an optically activeligand.

Likewise, the process for stereoselectively producing optically activenitro alcohols of the present invention is characterized in that, whenproducing optically active 1-(3-hydroxymethyl-4-hydroxyphenyl)-2-nitroalcohol derivatives, an aldehyde of the following formula (2-2),

in which R₁ and R₂ represent a hydrogen atom or a hydroxyl-protectivegroup, respectively, and they can either be independent of each other orform a ring together; R₄ represents a hydrogen atom, an alkyl group, ora hydroxymethyl group,

is reacted with a nitro alkane derivative of the following formula (3),

 R₄—CH₂—NO₂  (3)

in which R₄ represents a hydrogen atom, an alkyl group, or ahydroxymethyl group,

in the presence of a rare earth metal complex having an optically activeligand.

Likewise, the process for stereoselectively producing optically activenitro alcohols of the present invention is characterized in that, whenproducing optically active 1-(3,5-dihydroxyphenyl)-2-nitro alcoholderivatives, an aldehyde of the following formula (2-3),

in which R₁ and R₂ represent a hydrogen atom or a hydroxyl-protectivegroup, respectively, and they can either be independent of each other orform a ring together; R₄ represents a hydrogen atom, an alkyl group, ora hydroxymethyl group,

is reacted with a nitro alkane derivative of the following formula (3),

R₄—CH₂—NO₂  (3)

in which R₄ represents a hydrogen atom, an alkyl group, or ahydroxymethyl group,

in the presence of a rare earth metal complex having an optically activeligand.

Likewise, the process for stereoselectively producing optically activenitro alcohols of the present invention is characterized in that, whenproducing optically active 1-(4-hydroxyphenyl)-2-nitro alcoholderivatives, an aldehyde of the following formula (2-4),

in which R₁ represents a hydrogen atom or a hydroxyl-protective group;R₄ represents a hydrogen atom, an alkyl group, or a hydroxymethyl group,

is reacted with a nitro alkane derivative of the following formula (3),

R₄—CH₂—NO₂  (3)

in which R₄ represents a hydrogen atom, an alkyl group, or ahydroxymethyl group,

in the presence of a rare earth metal complex having an optically activeligand.

Suitable examples of the process for stereoselectively producingoptically active nitro alcohols of the present invention include thefollowing embodiments.

The process for stereoselectively producing optically active nitroalcohol derivatives characterized in that, when producing an opticallyactive 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivative of the formula(1-1) in which R₄ is a hydrogen atom and each of R₅ and R₆ is at-butyldimethylsiloxy group (optically active1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol), an aldehyde ofthe following formula (4)

is reacted with nitromethane in the presence of a rare earth metalcomplex having an optically active ligand.

The process for stereoselectively producing optically active nitroalcohol derivatives characterized in that, when producing an opticallyactive 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivative of the formula(1-1) in which R₄ is a hydrogen atom and each of R₅ and R₆ is a methylgroup (optically active 1-(3,4-dimethoxyphenyl)-2-nitroethanol), analdehyde of the following formula (5)

is reacted with nitromethane in the presence of a rare earth metalcomplex having an optically active ligand.

The process for stereoselectively producing optically active nitroalcohol derivatives characterized in that, when producing an opticallyactive 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivative of the formula(1-1) in which R₄ is a hydrogen atom and each of R₅ and R₆ is a benzylgroup (optically active1-(3,4-dibenzyloxyphenyl)-2-nitroethanol), analdehyde of the following formula (6)

is reacted with nitromethane in the presence of a rare earth metalcomplex having an optically active ligand.

The process for stereoselectively producing optically active nitroalcohol derivatives characterized in that, when producing an opticallyactive 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivative of the formula(1-1) in which R₄ is a hydrogen atom and each of R₅ and R₆ is a acetylgroup (optically active 1-(3,4-diacetoxyphenyl)-2-nitroethanol), analdehyde of the following formula (7)

is reacted with nitromethane in the presence of a rare earth metalcomplex having an optically active ligand.

The process for stereoselectively producing optically active nitroalcohol derivatives characterized in that, when producing an opticallyactive 1-(3,4-dihydroxyphenyl)-2-nitro alcohol derivative of the formula(1-1) in which R₄ is a hydrogen atom and R₅ and R₆ are cyclized with amethylene group (optically active α-nitromethyl-piperonyl alcohol), analdehyde of the following formula (8)

is reacted with nitromethane in the presence of a rare earth metalcomplex having an optically active ligand.

The process for stereoselectively producing optically active nitroalcohol derivatives characterized in that, when producing an opticallyactive 2,2-dimethyl-α-nitromethyl-1,3-benzodioxane-6-methanol of theformula (1-2) in which R₄ is a hydrogen atom and R₁ and R₂ are cyclized,an aldehyde of the following formula (9)

is reacted with nitromethane in the presence of a rare earth metalcomplex having an optically active ligand.

The process for stereoselectively producing optically active nitroalcohol derivatives characterized in that, when producing an opticallyactive 1-(3,5-dibenzyloxyphenyl)-2-nitroethanol of the formula (1-3) inwhich R₄ is a hydrogen

atom and each of R₁ and R₂ is a benzyl group, an aldehyde of thefollowing formula (10)

is reacted with nitromethane in the presence of a rare earth metalcomplex having an optically active ligand.

The process for stereoselectively producing optically active nitroalcohol derivatives characterized in that, when producing opticallyactive 1-(4-benzoyloxyphenyl)-2-nitroethanol of the formula (1-4) asdescribed in claim 1 in which R₄ is a hydrogen atom and R₁ is a benzoylgroup, an aldehyde of the following formula (11)

is reacted with nitromethane in the presence of a rare earth metalcomplex having an optically active ligand.

In the process for stereoselectively producing optically active nitroalcohol derivatives as described above, the rare earth metal complexesas above are preferably prepared from an alkoxide of Y, La, Nd, Sm, Eu,Gd, Tb, Dy, Pr or Yb, or a trichloride of these rare earth metals; anoptically active 1,1′-bi-2-naphthol derivative of the following formula(12)

or the following formula (13)

in which each of R₇ and R₈ independently represent a hydrogen atom, analkyl group of C₁-C₄, an ethynyl group, a trialkylsilylethynyl group, ora phenyl group, and R₇ can be at any position of 4, 5, 6 and 7, and R₈at any position of 4′, 5′, 6′ and 7′;

and an alkaline metal compound of lithium, sodium, or potassium.

Further, in the process for stereoselectively producing optically activenitro alcohol derivatives as described above, it is more preferable thatthe rare earth metal complexes to be used are prepared in such a waythat the composition ratio of the alkoxide or trichloride of the aboverare earth metals, the optically active 1,1′-bi-2-naphthol compound, andthe alkaline metal is within the range of 1:1-3:0-10.

The optically active 1-substituted phenyl-2-amino alcohol derivatives ofthe present invention are characterized by the following formula (14),

in which n and m represent the positive integers satisfying 0<n+m≦5; R₁and R₂ represent a hydrogen atom or a hydroxyl-protective group,respectively, and when n+m is 2 or more, R₁ and R₂ can either beindependent of each other or form a ring among R₁s, among R₂s, and amongR₁(s) and R₂(s); R₃ represents —(CH₂)₁—in which 1 represents 0, 1, or 3;R₄ represents a hydrogen atom, an alkyl group, or a hydroxymethyl group.

Suitable examples of the optically active 1-substituted phenyl-2-aminoalcohol derivatives of the present invention are the optically active1-(3,4-dihydroxyphenyl)-2-amino alcohol derivatives of the followingformula (14-1)

in which R₅ and R₆ represent a hydrogen atom or a hydroxyl-protectivegroup, respectively, and they can either be independent of each other orform a ring; R₄ represents a hydrogen atom, an alkyl group, or ahydroxymethyl group.

And the process for producing the optically active amino alcoholderivatives of the present invention is characterized in that, whenproducing optically active 1-substituted phenyl-2-amino alcoholderivatives, the optically active 1-substituted phenyl-2-nitro alcoholderivatives described above are stereoselectively reduced.

Pharmaceuticals such as optically active albutamin and sarmeterol can beproduced by reacting these optically active amino alcohol derivativeswith a carbonyl compound or an alkyl halide so as to introduce an alkylgroup etc. into the amino group, and then eliminatinghydroxyl-protective group; therefore, the optically active nitro alcoholderivatives and optically active amino alcohols of the present inventionare useful pharmaceutical intermediates.

Now the process for producing the optically active nitro alcoholderivatives of the present invention will be described below.

In general, nitro-aldol reaction between a benzaldehyde derivative and anitro alkane proceeds in the presence of a basic catalyst. Theasymmetric nitro-aldol reaction according to the present invention canbe carried out by the reaction of a benzaldehyde derivative and a nitroalkane in the presence of a rare earth metal complex having an opticallyactive ligand.

In this case, as a supplying source of an optically active ligand,preferable are optically active 1,1′-bi-2-napthol derivatives of thefollowing formula (12)

or the following formula (13)

in which R₇ and R₈ independently represent a hydrogen atom, an alkylgroup of C₁-C₄, an ethynyl group, a trialkylsilylethynyl group, or aphenyl group, and R₇ can be at any position of 4, 5, 6 and 7, and R₈ atany position of 4′, 5′, 6′ and 7′.

The process for preparing a rare earth metal complex solution can bebriefly illustrated by the following (reaction equation 1),

although the process is described in detail in the foregoing literature.This is exemplary of the process of this invention, and it is to beunderstood that the invention is not intended to be limited to thespecific process.

The present invention uses only one type of isomer, R-type or S-type, ofthe above optically active binaphthols. For the optically activebinaphthols, R₇ can be at any position of 3, 4, 5, 6 and 7, and R₈ atany position of 3′, 4′, 5′, 6′ and 7′, and it is found at present that,in terms of yield and optical purity, good results are obtainedparticularly from the optically active binaphthol having substituents at6 and 6′ positions.

Examples of R₇ and R₈ include a hydrogen atom; an alkyl group of methyl,ethyl, propyl, isopropyl, n-butyl, s-butyl, or t-butyl; a phenyl group;an alkenyl group; a trialkylsilylethynyl group (in this case, alkylincludes methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, or t-butyl,tow alkyls can be different from each other or can be the same); a cyanogroup; and a halogen; and any combination can be adopted.

Examples of the rare earth metals of the rare earth metal compoundsinclude Y, La, Nd, Sm, Eu, Gd, Tb, Dy, Pr, and Yb, any of the metals canbe used suitably.

Examples of the rare earth metal compounds include an alkoxide(including methoxide, ethoxide, propoxide, isopropoxide, n-butoxide,s-butoxide, and t-butoxide), a chloride (including both an anhydride anda hydride), and a nitrate, and any of them can be used preferably.

Examples of the alkaline metal compounds used for the preparation ofrare earth metal complexes include alkylalkaline metals (for example,methyllithium and n-butyllithium), alkaline metal hydroxides (forexample, lithium hydroxide, sodium hydroxide and potassium hydroxide).

Examples of solvents used in the preparation of a rare earth metalcomplex solution include THF; however, the present invention is notlimited to the specific solvent, and any solvents can be used as long asthey do not change the structure of the rare earth metal complexes.Examples other than THF include ether-based solvents (for example,diethyl ether and 1,4-dioxane), halogen-based solvents (for example,methylene chloride, chloroform, 1,1,1-trichloroethane andmonochlorobenzene), hydrocarbon-based solvents (for example, benzene,toluene, n-hexane and n-heptane), and fatty acid esters (for example,ethyl acetate and methyl acetate), in addition, polar solvents such asdimethyl sulfoxide, N,N′-dimethylformamide, etc. can also be used. Thesesolvents can be used in a single form or as a mixture of 2 or moretypes.

Examples of aldehydes used as a raw material for the process of thepresent invention include 2-hydroxybenzaldehyde, 3-hydroxybenzaldehyde,4-hydroxybenzaldehyde, 2,3-dihydroxybenzaldehyde,2,4-dihydroxybenzaldehyde, 2,5-dihydroxybenzaldehyde,2,6-dihydroxybenzaldehyde, 3,4-dihydroxybenzaldehyde,3,5-dihydroxybenzaldehyde, 2,3,4-trihydroxybenzaldehyde, 2,3,5-trihydroxybenzaldehyde, 2,3,6-trihydroxybenzaldehyde,2,4,5-trihydroxybenzaldehyde, 2,4,6-trihydroxybenzaldehyde,2-hydroxy-3-hydroxymethylbenzaldehyde,2-hydroxy-4-hydroxymethylbenzaldehyde,2-hydroxy-5-hydroxymethylbenzaldehyde,2-hydroxy-6-hydroxymethylbenzaldehyde,3-hydroxy-2-hydroxymethylbenzaldehyde,3-hydroxy-4-hydroxymethylbenzaldehyde,3-hydroxy-5-hydroxymethylbenzaldehyde,3-hydroxy-6-hydroxymethylbenzaldehyde,4-hydroxy-2-hydroxymethylbenzaldehyde,4-hydroxy-3-hydroxymethylbenzaldehyde,4-hydroxy-5-hydroxymethylbenzaldehyde,4-hydroxy-6-hydroxymethylbenzaldehyde, and the compounds as above ofwhich aromatic hydroxyl group is protected with a hydroxyl-protectivegroup (for example, t-butyldimethylsilyl group).

Examples of hydroxyl-protective groups used in the present inventioninclude a methyl group, a tetrahydropyranyl group, an allyl group, anisopropyl group, a t-butyl group, a benzyl group, an acetyl group, and atrimethylsilyl group which are described in Protective Groups in OrganicSynthesis.

Now the process for producing the optically active amino alcoholderivatives of the present invention will be described.

The optically active 1-substituted phenyl-2-amino alcohol derivatives ofthe present invention are synthesized by dissolving the correspondingoptically active 1-substituted phenyl-2-nitroethanol compounds in anorganic solvent, dispersing a catalytic hydrogen addition catalyst, andsubjecting the optically active 1-substituted phenyl-2-nitroethanolcompounds to hydrogen addition under hydrogen pressure.

Examples of the organic solvents include alcohols such as methanol,ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and esters suchas methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methylbutyrate, and ethyl butyrate; however, the present invention is notintended to be limited to the specific solvent, and these alcohols andesters can be used in a single form or as a mixture in desiredproportions.

For the catalytic hydrogen addition catalysts, usual hydrogen additioncatalysts are satisfactory, and the examples include Pt—C, Pd—C andPtO₂.

Although the present invention is not intended to be limited to thespecific amount of catalyst, considering the reaction time, 0.01 wt % ormore of catalyst is preferably added based on the substrate (nitroalcohol).

Further, although the present invention is not intended to be limited tothe specific reaction temperature, considering the intramoleculardehydration of nitro alcohols and the racemization of the products, thetemperature is preferably 50° C. and below.

Further, although the present invention is not intended to be limited tothe specific hydrogen pressure and preferably the pressure is in therange from 0.1 to 30 MPa, considering the production equipment, morepreferably in the range from 0.1 to 1 MPa.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is illustrated by the following embodiments andcatalyst preparation examples, however, it is to be understood that theinvention is not intended to be limited to the specific embodiments.

In each example, optical purity was determined by liquid chromatography(HPLC) (CHIRALPAK AD or CHIRALCEL OD by Daicel Chemical Industries,Ltd.). And ¹H-NMR was measured with JNM-EX-270 (270 MHz) by JEOL.

CATALYST PREPARATION EXAMPLE 1 Preparation of Rare Earth Metal ComplexSolution A0

58.0 mg (0.103 mmol) of(S)-6,6′-bis(triethylsilylethynyl)-1,1′-dihydroxy-2,2′-binaphthalene wasdried in a vacuum at 50° C. for 2 hours.(S)-6,6′-bis(trimethylsilylethynyl)-1,1′-dihydroxy-2,2′-binaphthalenewas dissolved in 880 μl of THF under an argon stream, and 172 μl of asolution of 11.3 mg (0.0344 mmol) of triisopropoxy samarium Sm (Oi-Pr)₃in 0.2mol/dm³ THF was added dropwise at 0° C. After stirring at roomtemperature for 30 minutes, 60 μl of a hexane solution of 1.72 mol/dm³n-BuLi (0.103 mmol) was added dropwise at 0° C. Then, the solution wasstirred at room temperature overnight and 35 μl of THF solutioncontaining water (0.035 mmol) was added, so as to prepare 0.03 mol/dm³THF solution of a complex catalyst (A0), as above.

CATALYST PREPARATION EXAMPLE 2 Preparation of Rare Earth Metal ComplexSolution A1

54 μl of hexane solution of 1.72 mol/dm³ n-BuLi (0.103 mmol) was addeddropwise to the rare earth metal complex solution A0, so as to prepare arare earth metal complex solution A1.

CATALYST PREPARATION EXAMPLE 3 Preparation of Rare Earth Metal ComplexSolution B0

A rare earth metal complex solution B0 was prepared following the sameprocedure as in the preparation of the rare earth metal complex solutionA0, except that lanthanum triisopropoxy La (Oi-Pr)₃ was used instead ofsamarium triisopropoxy Sm (Oi-Pr)₃.

CATALYST PREPARATION EXAMPLE 4 Preparation of Rare Earth Metal ComplexSolution B1

54 μl of hexane solution of 1.72 mol/dm³ n-BuLi (0.093 mmol) was addeddropwise to the rare earth metal complex solution B0, so as to prepare arare earth metal complex solution B1.

CATALYST PREPARATION EXAMPLE 5 Preparation of Rare Earth Metal ComplexSolution C0

A rare earth metal complex solution C0 was prepared following the sameprocedure as in the preparation of the rare earth metal complex solutionA0, except that dysprosium triisopropoxy Dy (Oi-Pr)₃ was used instead ofSm (Oi-Pr)₃.

CATALYST PREPARATION EXAMPLE 6 Preparation of Rare Earth Metal ComplexSolution C1

54 μl of hexane solution of 1.72 mol/dm³ n-BuLi (0.093 mmol) was addeddropwise to the rare earth metal complex solution C0, so as to prepare arare earth metal complex solution C1.

CATALYST PREPARATION EXAMPLE 7 Preparation of Rare Earth Metal ComplexSolution D0

A rare earth metal complex solution D0 was prepared following the sameprocedure as in the preparation of the rare earth metal complex solutionA0, except that gadolinium triisopropoxy Gd, (Oi-Pr)₃ was used insteadof Sm (Oi-Pr)₃.

CATALYST PREPARATION EXAMPLE 8 Preparation of Rare Earth Metal ComplexSolution D1

54 μl of hexane solution of 1.72 mol/dm³ n-BuLi (0.093 mmol) was addeddropwise to the rare earth metal complex solution D0, so as to prepare arare earth metal complex solution D1.

CATALYST PREPARATION EXAMPLE 9 Preparation of Rare Earth Metal ComplexSolution E0

A rare earth metal complex solution E0 was prepared following the sameprocedure as in the preparation of the rare earth metal complex solutionA0, except that praseodymium triisopropoxy Pr (Oi-Pr)₃ was used insteadof Sm (Oi-Pr)₃.

CATALYST PREPARATION EXAMPLE 10 Preparation of Rare Earth Metal ComplexSolution E1

54 μl of hexane solution of 1.72 mol/dm³ n-BuLi (0.093 mmol) was addeddropwise to the rare earth metal complex solution E0, so as to prepare arare earth metal complex solution E1.

CATALYST PREPARATION EXAMPLE 11 Preparation of Rare Earth Metal ComplexSolution F1

A metal complex solution was prepared following the same procedure as inthe preparation of the rare earth metal complex solution A0, except that(R)-1,1′-dihydroxy-2,2′-binaphthalene was used instead of(S)-6,6′-bis(triethylsilylethynyl)-1,1′-dihydroxy-2,2′-binaphthalene,after which 54 μl of hexane solution of 1.72 mol/dm³ n-BuLi (0.093 mmol)was added dropwise, so as to prepare a rare earth metal complex solutionF1.

EXAMPLE 1 Synthesis of(R)-1-(3,4-di(t-Butyldimethylsiloxy)phenyl)-2-nitroethanol

100 mg (0.26 mmol) of 3,4-di(t-butyldimethylsiloxy)benzaldehyde wasdissolved in 10 ml of THF under the atmosphere of argon at −40° C., and0.30 ml of rare earth metal complex solution A1 was mixed into thesolution. After stirring for 30 minutes, 79.3 mg (1.3 mmol) ofnitromethane was added dropwise to the mixture. After 67-hour reactiontime, 2 ml of 1 N aqueous solution of hydrochloric acid was added tostop the reaction. Then, after 50 ml of ethyl accetate was added, themixture was subjected to oil-water separation twice with 20 ml ofsaturated salt solution and once with 20 ml of water, and the ethylaccetate layer was dehydrated with sodium sulfate anhydride andconcentrated within evaporator, followed by the purification of theconcentrate by silica gel chromatography (n-hexane/acetone=10/1), afterwhich (R)-1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol with anoptical purity of 92% e.e. was obtained in a yield of 93%.

¹H-NMR (CDCl₃): δ 6.87-6.81 (m, 3H), 5.37-5.29 (m, 1H), 4.62-4.42 (m,2H), 2.62 (br, 1H), 0.99 (s, 9H), 0.98 (s, 9H), 0.20 (s, 6H).

EXAMPLE 2 Synthesis of(R)-1-(3,4-di(t-Butyldimethylsiloxy)phenyl)-2-nitroethanol

110 mg (0.2.9 mmol) of 3,4-di(t-butyldimethylsiloxy)benzaldehyde wasdissolved in 10 ml of THF under the atmosphere of argon at −40° C., and0.32 ml of rare earth metal complex solution A0 was mixed into thesolution. After stirring for 30 minutes, 88.5 mg (1.45 mmol) ofnitromethane was added dropwise to the mixture. After 67-hour reaction:time, (R)-1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol with anoptical purity of 92% e.e. was obtained in a yield of 74%.

EXAMPLE 3 Synthesis of (R)-1-(3,4-Dimethoxyphenyl)-2-nitroethanol

100 mg (0.55 mmol) of 3,4-dimethoxybenzaldehyde was dissolved in 10 mlof THF under the atmosphere of argon at −40° C., and 0.60 ml of rareearth metal complex solution A1 was mixed into the solution. Afterstirring for 30 minutes, 168 mg (2.75 mmol) of nitromethane was addeddropwise to the mixture. After 97-hour reaction time,(R)-1-(3,4-dimethoxyphenyl)-2-nitroethanol with an optical purity of 32%e.e. was obtained in a yield of 61%.

¹H-NMR (CDCl₃): δ 6.94-6.85 (m, 3H), 5.47-5.38 (m, 1H), 4.66-4.46 (m,2H), 3.90 (s, 3H), 3.89 (s, 3H), 2.73 (br, 1H)

EXAMPLE 4 Synthesis of (R)-1-(3,4-Dibenzyloxyphenyl)-2-nitroethanol

100 mg (0.30 mmol) of 3,4-dibenzyloxybenzaldehyde was dissolved in 10 mlof THF under the atmosphere of argon at −40° C., and 0.33 m′ of rareearth metal complex solution A1 was mixed into the solution. Afterstirring for 30 minutes, 91.6 mg (1.50 mmol) of nitromethane was addeddropwise to the mixture. After 75-hour reaction time,(R)-1-(3,4-dibenzyloxyphenyl)-2-nitroethanol with an optical purity 59%e.e. was obtained in a yield of 90%.

¹H-NMR (CDCl₃): δ 7.45-7.20 (m, 10H), 7.00-6.86 (m, 3H), 5.38-5.26 (m,1H), 5.17 (s, 2H), 5.16 (s, 2H), 4.57-4.38 (m, 2H), 2.67 (br, 1H)

EXAMPLE 5 Synthesis of (R)-1-(3,4-Diacetoxyphenyl)-2-nitroethanol

102 mg (0.43 mmol) of 3,4-diacetoxybenzaldehyde was dissolved in 10 mlof THF under the atmosphere of argon at −40° C., and 0.48 ml of rareearth metal complex solution A1 was mixed into the solution. Afterstirring for 30 minutes, 131 mg (2.15 mmol) of nitromethane was addeddropwise to the mixture. After 68-hour reaction time,(R)-1-(3,4-diacetoxyphenyl)-2-nitroethanol with an optical purity of 59%e.e. was obtained in a yield of 87%.

¹H-NMR (CDCl₃): δ 7.32-7.19 (m, 3H), 5.55-5.40 (m, 1H), 4.63-4.42 (m,2H), 2.62 (br, 1H), 2.30 (s, 3H), 2.29 (s, 3H)

EXAMPLE 6 Synthesis of(R)-1-(3,4-di(t-Butyldimethylsiloxy)phenyl)-2-nitroethanol

105 mg (0.28 mmol) of 3,4-di(t-butyldimethylsiloxy)benzaldehyde wasdissolved in 10 ml of THF under the atmosphere of argon at −40° C., and0.31 ml of rare earth metal complex solution D1 was mixed into thesolution. After stirring for 30 minutes, 85.5 mg (1.40mmol) ofnitromethane was added dropwise to the mixture. After 61-hour reactiontime, (R)-1-(3,4-di(t-butyldimethylsilxy)phenyl)-2-nitroethanol with anoptical purity of 87% e.e. was obtained in a yield of 86%.

EXAMPLE 7 Synthesis of(R)-1-(3,4-di(t-Butyldimethylsiloxy)phenyl)-2-nitroethanol

100 mg (0.26 mmol) of 3,4-di(t-butyldimethylsiloxy)benzaldehyde wasdissolved in 10 ml of THF under the atmosphere of argon at −40° C., and0.31 ml of rare earth metallcomplex solution B1 was mixed into thesolution. After stirring for 30 minutes, 79.3 mg (1.30 mmol) ofnitromethane was added dropwise to the mixture. After 66-hour reactiontime, (R)-1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol with anoptical purity of 79% e.e. was obtained in a yield of 89%.

EXAMPLE 8 Synthesis of(R)-1-(3,4-di(t-Butyldimethylsiloxy)phenyl)-2-nitroethanol

100 mg (0.26mmol) of 3,4-di(t-butyldimethylsiloxy)benzaldehyde wasdissolved in 10 ml of THF under the atmosphere of argon at −40° C., and0.31 ml of rare earth metal complex solution E1 was mixed into thesolution. After stirring for 30 minutes, 79.3mg (1.30mmol) ofnitromethane was added dropwise to the mixture. After 66-hour reactiontime, (R)-1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol with anoptical purity of 84% e.e. was obtained in a yield of 86%.

EXAMPLE 9 Synthesis of(R)-1-(3,4-di(t-Butyldimethylsiloxy)phenyl)-2-nitroethanol

102 mg (0.27 mmol) of 3,4-di(t-butyldimethylsiloxy)benzaldehyde wasdissolved in 10 ml of THF under the atmosphere of argon at −40° C., and0.30 ml of rare earth metal complex solution C1 was mixed into thesolution. After stirring for 30 minutes, 82.4 mg (1.35 mmol) ofnitromethane was added dropwise to the mixture. After 66-hourreactionitime,(R)-1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol with anoptical purity of 68% e.e. was obtained in a yield of 72%.

EXAMPLE 10 Synthesis of(S)-1-(3,4-di(t-Butyldimethylsiloxy)phenyl)-2-nitroethanol

The rare earth metal complex solution F1 (10 ml) and 0.80 g (13.0 mmol)of nitromethane were mixed and stirred together for 30 minutes under theatmosphere of nitrogen. A solution of 1.00 g (2.6 mmol) of3,4-di(t-butyldimethylsiloxy)benzaldehyde dissolved in 20 ml of THF wasadded dropwise to the mixture. After 24-hour reaction time,(S)-1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol with,anoptical purity of 93% e.e. was obtained in a yield of 85%.

EXAMPLE 11 Synthesis of (R)-α-Nitromethyl-piperonyl alcohol

(R)-α-nitromethyl-piperonyl alcohol with an optical purity of 73% e.e.was obtained from piperonal using the rare earth metal complex solutionA1 under the atmosphere of argon at −40° C. after 50-hour reaction time.

¹H-NMR (CDCl₃): δ 6.90-6.82 (m, 3H), 5.99 (s, 2H), 5.41-5.35 (m, 1H),4.62-4.43 (m, 2H), 2.70 (br, 1H)

EXAMPLE 12 Synthesis of Optically Active1-(3,5-di(t-Butyldimethylsiloxy)phenyl)-2-nitroethanol

100 mg (0.26 mmol) of 3,5-di(t-butyldimethylsiloxy)benzaldehyde wasdissolved in 10 ml of THF under the atmosphere of argon at −40° C., and0.30 ml of rare earth metal complex solution A1 was mixed into thesolution. After stirring for 30 minutes, 159 mg (2.6 mmol) ofnitromethane was added dropwise to the mixture. After 140-hour reactiontime, optically active1-(3,5-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol with an opticalpurity of 62% e.e. was obtained in a yield of 93%.

¹H-NMR (CDCl₃): δ 6.86-6.83 (m, 3H), 5.34 (m, 1H), 4.57 (dd, J=13.3, 9.4Hz, 1H), 4.46 (dd, J=13.3, 3.1 Hz, 1H), 2.64 (d, J=3.5 Hz, 1H), 0.9:9(s, 9H), 0.98 (s, 9H), 0.20 (s, 12H)

EXAMPLE 13 Synthesis of Optically Active1-(3,5-Dibenzyloxyphenyl)-2-nitroethanol

100 mg (0.30 mmol) of 3,5-dibenzyloxydibenzaldehyde was dissolved in 10ml of THF under the atmosphere of argon at −40° C., and 0.35 ml of rareearth metal complex solution A1 was mixed into the solution. Afterstirring for 30 minutes, 183 mg (3.0 mmol) of nitromethane was addeddropwise to the mixture. After 71-hour reaction time, optically active1-(3,5-dibenzyloxyphenyl)-2-nitroethanol with an optical purity of 68%e.e. was obtained in a yield of 84%.

¹H-NMR (CDCl₃): δ 7.45-7.30 (m, 10H), 6.65-6.58 (m, 3H), 5.42-5.36 (m,1H), 5.04 (s, 4H), 4.62-4.45 (m, 2H), 2.74 (d, 1H)

EXAMPLE 14 Synthesis of Optically Active1-(3,5-Dibenzyloxyphenyl)-2-nitroethanol

100 mg (0.3 mmol) of 3,5-dibenzyloxydibenzaldehyde was dissolved in 10ml of THF under the atmosphere of argon at −40° C., and 0.32 ml of rareearth metal complex solution A1 was mixed into the solution. Afterstirring for 30 minutes, 183 mg (29.9 mmol) of nitromethane was addeddropwise to the mixture. After 88-hour reaction time, optically active1-(3,5-dibenzyloxyphenyl)-2-nitroethanol with an optical purity of 88%e.e. was obtained in a yield of 100%. ¹-H-NMR (CDCl₃): δ 7.45-7.30 (m,10H), 6.65-6.58 (m, 3H), 5.42-5.36 (m, 1H), 5.04 (s, 4H), 4.62-4.45 (m,2H), 2.74 (d, 1H)

EXAMPLE 15 Synthesis of Optically Active1-(3,5-Diacetoxyphenyl)-2-nitroethanol

102 mg (0.43 mmol) of 3,5-diacetoxybenzaldehyde was dissolved in 10 ml,of THF under the atmosphere of argon at −40° C., and 0.45 ml of rareearth metal complex solution A1 was mixed into the solution. Afterstirring for 30 minutes, 262 mg (4.3 mmol) of nitromethane was addeddropwise to the mixture. After 44-hour reaction time, optically active1-(3,5-diacetoxyphenyl)-2-nitroethanol with an optical purity of 86%e.e. was obtained in a yield of 89%.

¹H-NMR (CDCl₃): δ 7.07 (d, 2H), 6.91 (t, 1H), 5.48-5.41 (m, 1H),4.61-4.48 (m, 2H), 3.03 (d, 1H), 2.29 (s, 6H)

EXAMPLE 16 Synthesis of Optically Active1-(4-t-Butyldimethylsiloxy-3-t-butyldimethylsiloxymethylphenyl)-2-nitroethanol

The rare earth metal complex solution A1 (0.10 ml) and 66 mg (1.07 mmol)of nitromethane were stirred at −40° C. for 30 minutes, then 0.39 ml ofsolution of 41 mg (0.11 mmol) of4-t-butyldimethylsiloxy-3-t-butyldimethylsiloxymethylbenzaldehyde in THFwas added dropwise to the mixture. After 69-hour reaction time,optically active1-(4-t-butyldimethylsiloxy-3-t-butyldimethylsiloxymethylphenyl)-2-nitroethanolwith an optical purity of 37% e.e. was obtained in a yield of 35%.

¹H-NMR (CDCl₃): δ 7.47 (d, j=2.0 Hz, 1H) , 7.16 (dd, j=8.5, 2.0 Hz, 1H),6.76 (d, j=8.5 Hz, 1H), 5.41 (dd, j=9.5, 3.5, 3.0 Hz, 1H), 4.74 (s,:2H), 4.61 (dd, j=13.5, 9.0 Hz, 1H), 4.48 (dd, j=13.5, 3.0 Hz, 1H), 2.65(d, j=3.5 Hz, 1H), 1.00 (s, 9H), 0.96 (s, 9H), 0.22 (s, 6H), 0.11 (s,6H)

EXAMPLE 17 Synthesis of Optically Active2,2-Dimethyl-α-nitromethyl-1,3-benzodioxane-6-methanol

100 mg (0.52 mmol) of 2,2-dimethyl-1,3-benzodioxane-6-acetoaldehyde wasdissolved in 1.9 ml of THF under the atmosphere of argon at −40° C., andthe rare earth metal complex solution A1 was mixed into the solution.After stirring for 30 minutes, 318 mg (5.2 mmol) of nitromethane wasadded dropwise to the mixture. After 61-hour reaction time, opticallyactive 2,2-dimethyl-α-nitromethyl-1,3-benzodioxane-6-methanol with anoptical purity of 87% e.e. was obtained in a yield of 86%.

EXAMPLE 18 Synthesis of Optically Active1-(4-t-Butyldimethylsiloxy-3-t-butyldimethylsiloxymethylphenyl)-2-nitroethanol

The rare earth metal complex solution B1 and 65 mg (1.07 mmol) ofnitromethane were stirred at −40° C. for 30 minutes, then 0.40 ml ofsolution of 42 g (0.11 mmol) of4-t-butyldimethylsiloqxy-3-t-butyldimethylsiloxymethylbenzaldehyde inTHF was added dropwise to the mixture. After 67-hour reaction time,optically active1-(4-t-butyldimethylsiloxy-3-t-butyldimethylsiloxymethylphenyl)-2-nitroethanolwith an optical purity of 30% e.e. was obtained in a yield of 30%.

EXAMPLE 19 Synthesis of Optically Active1-(4-Benzoyloxy-3-benzoyloxymethylphenyl)-2-nitroethanol

The rare earth metal complex solution A1 and 149 mg (2.44 mmol) ofnitromethane were stirred at −40° C. for 30 minutes, then 0.89 ml ofsolution of 88 mg (0.24 mmol) of4-benzoyloxy-3-benzoyloxymethylbenzaldehyde in THF was added dropwise tothe mixture. After 69-hour reaction time, optically active1-(4-benzoyloxy-3-benzoyloxymethylphenyl)-2-nitroethanol with an opticalpurity of 64% e.e. was obtained in a yield of 86%.

EXAMPLE 20 Synthesis of Optically Active1-(4-Benzoyloxyphenyl)-2-nitroethanol

Optically active 1-(4-benzoyloxyphenyl)-2-nitroethanol with an opticalpurity of 50% e.e. was obtained from 4-benzoyloxybenzaldehyde using therare earth metal complex solution F1 under the atmosphere of nitrogen at−30° C. after 24-hour reaction time.

EXAMPLE 21 Synthesis of Optically Active1-(4-Benzoyloxyphenyl)-2-nitropropanol

(S,S)-1-(4-benzoyloxyphenyl)-2-nitropropanol (30% e.e.), the threoform/erythro form ratio is 1.8/1.0, was obtained from4-benzoyloxybenzaldehyde and nitroethane using the rare earth metalcomplex solution F1 under the atmosphere of nitrogen at −30° C. after24-hour reaction time.

EXAMPLE 22 Synthesis of(R)-(−)-1-(3,4-di(t-Butyldimethylsiloxy)phenyl)-2-aminoethanol

100 mg of optically active1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol obtained inexample 1 was dissolved in 10 ml of methanol, and 10 mg of 10% Pd/C wasadded to the solution, after which the mixture was reacted at 20° C.under the hydrogen pressure of 0.1 MPa for 20 hours, so as to obtain89.3 mg of the intended compound (in a yield of 96%, with an opticalpurity of 94% e.e.). IR (neat) cm⁻¹: 3859, 2928

¹H-NMR (CDCl₃): δ 6.85-6.76 (m, 3H), 4.54 (dd, j=8.0, 4.0 Hz, 1H), 2.97(dd, j=12.0, 4.0 Hz, 1H), 2.81 (dd, j=12.0, 8.0 Hz, 1H), 0.98 (5, 18H),0.19 (s, 12H) ¹³C-NMR (CDCl₃, 97.9 MHz): 146.7, 146.3, 135.5, 120.8,118.8, 73.7, 49.1, 25.9, 18.4, −4.1

[α]²⁵ _(D)=−21.9 (cl.15, CHCl₃).

EXAMPLE 23 Synthesis of(S)1-1-(3,4-di(t-Butyldimethylsiloxy)phenyl)-2-aminoethanol

98 mg of (S)-1-(3,4-di (t-butyldimethylsiloxy)phenyl)-2-nitroethanolobtained in example 10 was dissolved in 10 ml of methanol, and 10 mg of10% Pd/C was added to the solution, after which the mixture was reactedat 20° C. under the hydrogen pressure of 0.3 MPa for 5 hours, so as toobtain 85 mg of the intended compound.

[α]²⁵ _(D)=+21.5 (cl.10, CHCl₃).

EXAMPLE 24 Synthesis of Optically Active1-(3,5-Dibenzoyloxyphenyl)-2-aminoethanol

The intended compound with an optical purity of 12% e.e. was obtained inalyield of 12% from the optically active1-(3,5-dibenzoyloxyphenyl)-2-nitroethanol obtained in example 14 using10% Pd/C.

[α]²⁵ _(D)=−2.3 (c0.32, EtOH)

EXAMPLE 25 Synthesis of Optically Active1-(4-t-Butyldimethylsiloxy-3-t-butyldimethylsiloxymethylphenyl)-2-aminoethanol

The intended compound was obtained from the optically active1-(4-t-butyldimethylsiloxy-3-t-butyldimethylsiloxymethylphenyl)-2-nitroethanolobtained in example 18 using 10% Pd/C.

[α]²⁵ _(D)=−2.9 (c0.35, EtOH)

EXAMPLE 26 Synthesis of Optically Activeα-Aminomethyl-2,2-dimethyl-1,3-benzodioxane-6-methanol

The intended, compound was obtained from the optically active2,2-dimethyl-α-nitromethyl-1,3-benzodioxane-6-methanol obtained inexample 17 using 10% Pd/C.

[α]²⁵ _(D)=−2.2 (c0.25, EtOH)

EXAMPLE 27 Synthesis of (R)-Albutamin

89.3 mg of (−)-1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-aminoethanol,50.0 mg of 4-(4-methoxymethoxyphenyl)butanoic acid,diethylphosphorylcyanide, and triethylamine were dissolved inN,N-dimethylformamide at 0° C., reacted at room temperature, so as toobtain 108.6 mg (in a yield of 82%) of amide compound. The amidecompound obtained was reduced with lithium aluminium halide in an ethersolvent at reflux temperature, so as to quantitatively obtain amine. And55.6 mg of (R)-albutamin which is the intended compound was obtained bydeprotecting the hydroxyl-protective group of the amine in amethanol—THF solvent at room temperature using hydrochloric acid.

[α]²⁵ _(D)=−17 (c1.15, EtOH)

EXAMPLE 28 Synthesis of (R)-Sarmeterol

Amine was obtained from the optically active2,2-dimethyl-α-aminomethyl-1,3-benzodioxane-6-methanol synthesized inexample 26 and 6-(1-phenyl-butoxy) hexaaldehyde through subjecting themto reduction and amination, then the hydroxyl-protective group of theamine compound was deprotected using hydrochloric acid, so as to obtainthe intended compound, (R)-sarmeterol. The angle of rotation wasmeasured using the compound's salt of hydroxy naphthoic acid.

[α]²⁴ _(D)=−3.1 (c0.30, MeOH)

Industrial Availability

As described above, according to the present invention, optically active1-substituted phenyl-2-nitro alcohol derivatives and optically active1-substituted phenyl-2-amino alcohol derivatives, which are useful aspharmaceutical intermediates, and, in addition, the process forproducing these compounds can be provided using a specific group of rareearth metal complexes.

Specifically, according to the present invention, optically active1-substituted phenyl-2-nitro alcohol derivatives which are used as amaterial for pharmaceuticals, such as (R)-albutamin, have beensynthesized, and the process for producing thereof has been established.

At the same time, the process for producing optically active1-substituted phenyl-2-amino alcohol derivatives which are to becomeuseful intermediates of pharmaceuticals from optically active1-substituted phenyl-2-nitro alcohol derivatives has been established,and the process for producing pharmaceuticals, (R)-albutamin and(R)-sarmeterol, from optically active 1-substituted phenyl-2-aminoethanol derivatives has been established.

What is claimed is:
 1. An optically active alcohol of the followingformula (1-1)

in which R₅ and R₆ both represent a t-butyldimethylsilyl group,respectively; R₄ represents a hydrogen atom; and * represents anoptically active site.